PROJECT SUMMARY/ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma (KS), is unique among human herpesviruses in that it is not ubiquitous in human populations, but rather shows marked geographic hotspots in prevalence, being particularly common in sub-Saharan Africa (SSA). Moreover, there is variation in prevalence even between geographically proximate locations within the same population in SSA. This strongly suggests the presence of modifiable environmental factors that facilitate and maintain high levels of transmission in SSA and we posit that malaria infection is a key underlying factor. We provide extensive published and preliminary data supporting an interaction between malaria infection in children and KSHV seroprevalence. We hypothesize that malaria infection in children increases their susceptibility to KSHV through alterations in immune function or expansion of KSHV cellular targets or both. For children that are already KSHV infected, malaria infection could lead to viral reactivation resulting in higher viral loads in peripheral blood, higher frequency of shedding or both. The General Population Cohort (GPC) in rural Uganda is a longitudinal study investigating the trends and determinants of the HIV epidemic, as well as non- communicable disease risk factors. We found that KSHV seroprevalence in the GPC is among the highest ever reported (>90%) and children are infected at an early age (~30% by 3 years). The early age of KSHV infection, the endemic malaria transmission and the high levels of KSHV seroprevalence in the Ugandan GPC provides us with a unique opportunity to directly test our hypothesis. We will do this by enrolling a prospective infant cohort within the GPC determining the effect of P. falciparum on the establishment of KSHV infection; characterizing immune phenotype in children prior to KSHV infection and evaluate effects of P. falciparum on KSHV reactivation. In this proposal, we will capitalise on an ongoing substantive research program on KSHV and will embed the proposed work within a long-standing population-based cohort in rural Uganda, with a substantial body of existing data. The proposed work will address the profound knowledge gap regarding factors that influence KSHV transmission. This may, in the future, lead to the development of interventions to reduce transmission and thereby reduce the burden of KS.